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Evolution of Type 2 Diabetes:
The Time for Insulin is Now



Introduction

In the United States, there are currently15.7 million people with diabetes. Of these, 5.4 million people are unaware they have the disease. Each year, another 800,000 (2,200 per day) Americans develop diabetes. The consequences of improper management of diabetes is very dramatic, according to Paul S. Jellinger, MD, FACE, clinical professor in the department of medicine of Miami School of Medicine in Miami, Florida. For example, 57,000 deaths are directly, and 193,000 deaths indirectly, attributed to diabetes each year. Diabetes leads to 24,000 cases of blindness, 28,000 cases of end stage renal disease, and 67,000 lower limb amputations.

Most patients with type 2 diabetes patients will die “not directly from a diabetic complication such as renal failure or even complications of an amputation,” said Dr. Jellinger, adding, “they’ll die from a heart attack or stroke.” Patients with diabetes have “at least a 2–4-fold increase in coronary artery
disease, a 2–4 fold increase in stroke, and are 2–8 fold more likely to experience heart failure,” further explained Dr. Jellinger. It has been estimated that 60%–80% of all diabetic- related deaths are associated with vascular diseases.

The cost of diabetes is very high. Using heathcare costs from 1993–1995, Dr. Jellinger informed the audience that diabetes alone accounts for $8,000 to $10,000 in medical costs over a 3-year period. Most medical costs however, are due to complications associated with diabetes (i.e., hypertension, heart disease) and account for $40,000–$50,000 over a 3-year period.

Slow Progressive Development of Type 2 Diabetes
As type 2 diabetes develops, the first noticeable change is increased postprandial blood sugar levels. This increase is generally in response to an increase in insulin resistance and b-cell dysfunction (Figure 1). In most cases, these changes go unnoticed for up to 10 years, at which time b-cells have depleted by about 50% and high fasting glucose levels are observed.

Insulin release in healthy individuals has two phases. The first phase occurs within minutes of a meal followed by the second delayed response. In type 2 diabetes, there is no first phase release and a blunted second phase release. Therefore, treatment with insulin therapy should target insulin release that better mimics the normal response.

Treatment of Type 2 Diabetes
Earliest stages of diabetes can often be controlled by nutrition and fitness therapy. In later stages, however, the ability to achieve an A1C less than 7 declines dramatically. This is partially due to our inability to properly use the treatment options currently available. “We need to learn how to use our therapies better, we have excellent tools but there is something between these therapies and execution that is not allowing patients on oral agents and insulin to get to the A1C that those on diet are able to achieve,” said Dr. Jellinger, adding, “overall, only about 40% of patients taking a combined diet, oral, and insulin therapy will have A1C levels less than 7%; so we have a way to go with our therapies.”

“Diabetes management in 2002 has a huge array of insulin formulations, monitoring devices and medication classes,” stated Dr. Jellinger, further adding “as we understand the physiology of type 2 diabetes we have tools now that can correct the abnormal physiologic state such as basal insulins that allow your patient to wake up with a normal fasting glucose, and other agents that reduce postprandial excursions. One of the greatest concerns with type 2 diabetes is the complications that are associated with this disease. The best way to prevent these complications is to promote early diagnosis and early aggressive treatment of type 2 diabetes.”



Diagnosing and Establishing Treatment Goals in Patients with Type 2 Diabetes

Helena Rodbard, MD, FACE, FACP, president of the American College of Endocrinology in Rockville, Maryland began her presentation by adding to the statistics provided by Dr. Jellinger. Dr. Rodbard said that 155 million people worldwide had diabetes in 1995 and by the year 2020, it is estimated to increase to 300 million people. Of the 16 million patients with diabetes in the United States, about one-third do not know they have diabetes and type 2 diabetes accounts for about 90%of those undiagnosed cases. Since type 2 diabetes is a slow progressive disease approximately half of these patients already have complications at the time of diagnosis. The increase in type 2 diabetes is primarily due to a 60% increase in adult obesity. According to the CDC, type 2 diabetes is developing in younger adults and is beginning to be diagnosed in teenagers and even in children.

For these reasons, AACE formed a panel of diabetes experts who convened in the summer of 2001 and led to the revised guidelines for the management of diabetes. These guidelines were recently published in the January/February issue of Endocrine Practice. The “AACE Consensus Conference on Guidelines for Glycemic Control” was organized to answer five questions. They are:

1. What is the Goal of Diabetes Management?
The goal of diabetes management is to prevent complications, especially cardiovascular complications. In order to achieve this, the diagnosis of type 2 diabetes needs to be earlier. Persons beginning to show impaired glucose tolerance have twice the cardiovascular mortality rates compared to healthy individuals. By the time they have type 2 diabetes, the mortality rate is 3–4 fold higher.

2. To what Extent Does Glycemic Control Achieve that Goal?
To what extent glycemic control prevents complications was well established in two landmark studies: the DCCT study involving type 1 diabetes and the UKPDS study with type 2 diabetes. Dr. Rodbard said “those studies concluded that a 1% reduction in A1C results in a 14% drop in microvascular complications.” Dr. Rodbard explained to the audience that trying to determine what is a ‘safe’ A1C level is difficult, but based on a variety of epidemiological studies, it was determined that macrovascular complications begin when A1C is less than 6.5%.

The strong relationship between A1C and cardiovascular complications is further supported by data showing that poor glycemic control, as measured by fasting glucose and 2-hour postprandial glucose, increases hazard ratios for death. In general, Dr. Rodbard said that fasting and preprandial blood sugar levels should be less than 110 mg/dL and postprandial levels less than 135–140 mg/dL to reduce cardiovascular complications.

3. What Factors Should be Used to Assess Glycemic Control?
Based largely on the standards set by the International Diabetes Association, an evidence-based consensus was formed by the AACE panel to establish primary and secondary assessment guidelines. Primary assessment should be A1C and secondary assessment should include fasting, preprandial, and postprandial glucose levels.

4. What are the Guidelines for Attaining Glycemic Control?
The guidelines recommend that A1c levels should be maintained below 6.5%. For secondary assessment, ideal glucose levels for fasting and preprandial glucose levels should be under 100-110 mg/dL while postprandial glucose levels should be under 135 mg/dL. Attempts to maintain these levels in patients with type 2 diabetes may be challenging. Dr. Rodbard said that the slow, often silent, progression of type 2 diabetes requires that early detection and early aggressive treatment, including treatment of co-morbidities be used. Further, treatment should include a combination of diet, exercise and medication.

5. What Further Recommendations are Needed Regarding Glycemic Control and Reduction of Complications?
Unlike previous guidelines, the AACE state that screening should begin at age 30 years, instead of waiting to age 45 or more. People who should be screened early include persons with: a family history of diabetes; family history of cardiovascular disease; overweight, sedentary lifestyle; minorities; previously identified impaired glucose tolerance or impaired fasting glucose; hypertension; increased triglycerides, low HDLs; history of gestational diabetes or infant weight greater than 9 pounds; and polycystic ovary syndrome.

Conclusion
Dr. Rodbard ended her presentation by stating that the AACE guidelines are a work in progress and in time, revisions will be made. One of the wonderful things about medicine is that it is always changing, and “there is always more to learn and that’s what we are all doing,” said Dr. Rodbard.


Insulin Strategies to Obtain Tight Glycemic Control

As with the AACE guidelines, “our understanding of the pathophysiology of type 2 diabetes is also a work in progress,” stated Derek Le Roith, MD, PhD, FACP, chief of the Clinical Endocrinology Branch of the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health in Bethesda, Maryland. As previously discussed by Dr. Jellinger, there is a strong relationship between insulin sensitivity, insulin secretion, and b cell function. The progression of the disease as you have heard is because of the dysfunction of the b-cell,” said Dr. Le Roith and stressed that the key words are cell dysfunction, not cell death. The intracellular changes that account for b-cell dysfunction are complex but equally important are the effects that abnormal insulin secretion have on other organs. The ‘glucotoxicity’ and ‘lipotoxicity’ that develop can lead to significant changes in the liver, intestines, muscle, and pancreas. For example, decreased insulin secretion leads to increased fatty acids in the muscle that in turn leads to stimulation of kinases and other enzymes that further interfere with insulin receptor signaling and glucose uptake. The complex interactions of glucose and lipids in the various organs was stressed by Dr. Le Roith to provide the audience with a better understanding of the need for multiple therapeutic regimens to treat type 2 diabetes. Furthermore, all of these changes in the various organs are progressive, stressing the need to treat these patients early and more aggressively.

Treating Type 2 Diabetes
Dr. Le Roith introduced the subject of treatment by providing a case study involving a 66-year- old black female with type 2 diabetes. She was diagnosed with diabetes 10 years ago and has many of the typical type 2 diabetic symptoms including: overweight, some dyslipidemia, some ankle edema, fasting glucose of 188 mg/dL, and A1C of 8.6% while on a therapy of diet/exercise and ramipril/hydrochlorothiazide, glimepiride, and metformin. Switching to a triple oral therapy of glimepiride, metformin, and pioglitazone led to a slight decrease in A1C (7.9%) and fasting glucose (172 mg/dL). As with most type 2 diabetes patients, Dr. Le Roith said it is time for this patient to be placed on insulin therapy.

Basal Insulin Control of Type 2 Diabetes
A common insulin analog used to control basal glucose is NPH. Unfortunately, it is limited by its peak action, short duration of action, and variable bioavailability which can lead to nocturnal hypoglycemia, and variability in blood glucose. A more appropriate basal insulin therapy is the new long-acting insulin analog insulin-glargine. Compared to other insulin analogs, it does not peak but provides a smooth, slow continuous release up to 24 hours (Figure 2). It has a clinical efficacy equivalent to NPH with significantly less nocturnal hypoglycemia (Diabetes 2000;49:2141–2148).

Practical guidelines for starting basal insulin in type 2 diabetes should begin with a single evening dose of about 10 units while continuing on their oral agents at the same dosage (eventually reducing). The dose of the basal insulin should be adjusted based on fasting blood glucose. For example, if fasting blood glucose is 120–140 mg/dL, increase the dose by 2 units. If fasting blood glucose is 140–180 mg/dL increase the dose by 4 units, and if fasting blood glucose is greater than 180 mg/dL increase the dose by 6 units. This should continue until a target blood glucose level is reached (i.e., less than 120 mg/dL). Keep in mind that each patient should be dosed individually and these are general guidelines.

Postprandial Insulin Control in Type 2 Diabetes
There are several insulin analogs available to control postprandial glucose, including insulin-aspart and insulin-lispro. Dr. Le Roith discussed recent advances in pulmonary insulin delivery that have the advantage of not requiring injections. Overall, studies with pulmonary insulin delivery have shown it to be effective with a rapid onset of action and a short duration. These studies are currently still being performed to ensure its efficacy and safety, as well as to determine if insulin affects the pulmonary system.

Conclusion
Dr. Le Roith ended his presentation by saying, “in the future it is possible that we would use a basal insulin, a single injection, and then one would be able to use short-acting insulins either by injection, which is with a pen as it is being used today, or the possibility of using inhaled insulin three times a day prior to each meal.” As type 2 diabetes progresses, it is inevitable that the patient will have to be put on insulin therapy. By providing a safe and effective treatment that controls both basal and postprandial glucose properly, the improvements in blood glucose control can help us reach target HbA1C and help prevent the long-term complications associated with type 2 diabetes.

 


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